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Vasopressin and its analogues for the treatment of refractory hypotension in neonates

  1. Binoy Shivanna1,
  2. Danielle Rios1,
  3. Joseph Rossano2,
  4. Caraciolo J Fernandes1,
  5. Mohan Pammi1,*

Editorial Group: Cochrane Neonatal Group

Published Online: 28 MAR 2013

Assessed as up-to-date: 15 JUL 2012

DOI: 10.1002/14651858.CD009171.pub2


How to Cite

Shivanna B, Rios D, Rossano J, Fernandes CJ, Pammi M. Vasopressin and its analogues for the treatment of refractory hypotension in neonates. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD009171. DOI: 10.1002/14651858.CD009171.pub2.

Author Information

  1. 1

    Baylor College of Medicine, Section of Neonatology, Department of Pediatrics, Houston, Texas, USA

  2. 2

    The Children's Hospital of Philadelphia, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

*Mohan Pammi, Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, 77030, USA. mohanv@bcm.tmc.edu. suseela12@hotmail.com.

Publication History

  1. Publication Status: New
  2. Published Online: 28 MAR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms
 

Description of the condition

Hypotension is a significant problem in preterm, septic, and post-surgical neonates. Symptomatic hypotension (hypotension requiring treatment) is associated with significant morbidity. In a case-control study of 156 extremely low birth weight infants (ELBW, birth weight less than 1000 g), symptomatic hypotension in the first 72 hours of life was associated with a severe grade of intraventricular hemorrhage (IVH), higher mortality, increased hearing loss, and adverse neurodevelopmental outcomes (Fanaroff 2006). In preterm infants, hypotension may be associated with neonatal cerebral injury resulting in adverse long-term neurodevelopmental outcomes (Low 1993; Goldstein 1995).

Normal blood pressure is defined by blood pressure between the 10th and 90th percentiles that are appropriate for postmenstrual age (Nuntnarumit 1999). The 10th percentile for the mean blood pressure approximately equals the gestational age in the first 48 hours of life (Hegyi 1994). Impairment of cerebral blood flow and associated cerebral injury at mean blood pressures of less than 30 mmHg has been reported, which has prompted some neonatologists to treat neonates with a mean BP below this threshold (Miall-Allen 1987; Tsuji 2000; Munro 2004). Therapeutic measures for neonatal hypotension include volume expansion (bolus of crystalloids or colloids), inotropic agents (catecholamines: dopamine, dobutamine, epinephrine or rarely norepinephrine) and corticosteroids (hydrocortisone or dexamethasone) (Pladys 1999; Al-Aweel 2001; Seri 2001; Dempsey 2006). Strong evidence to support one therapy over the other for the treatment of neonatal hypotension is lacking. Evidence is insufficient not only regarding the use of fluid boluses in the treatment of neonatal hypotension, but also with the type of fluid used (colloid or crystalloid) (Osborn 2004). Dopamine increases mean blood pressure better than fluid boluses (Osborn 2001) or dobutamine (Subhedar 2003), but it does not decrease mortality or adverse neurodevelopmental outcomes. The efficacy of epinephrine (Paradisis 2004) and corticosteroids (Subhedar 2007) in the treatment of neonatal hypotension in improving the outcomes of mortality or adverse neurodevelopmental outcomes is yet to be proven. 

Refractory hypotension in the newborn is defined as a hypotension with signs of inadequate perfusion despite volume expansion and administration of inotropic agents and/or corticosteroids (Sarkar 2007; Baker 2008; Bidegain 2010). Refractory hypotension has an estimated mortality of about 50% (Bidegain 2010; Meyer 2006a; Meyer 2006b) and can result in significant morbidity in critically ill neonates (Meyer 2006b; Rodriguez-Nunez 2006; Leone 2008). Therefore, optimization of blood pressure and tissue perfusion in refractory hypotension may be crucial to improve clinical outcomes.

 

Description of the intervention

Arginine vasopressin (AVP) is a neuropeptide hormone secreted by the posterior pituitary that regulates sodium homeostasis and serum osmolality. AVP is released into the circulation in response to high plasma osmolality or as a baroreceptor response to hypovolemia. In health, AVP secretion is tightly regulated by changes in serum osmolality. In contrast, the baroreceptor-mediated regulation of AVP secretion is regulated by a fall in blood pressure (> 10%) (Mutlu 2004).

Terlipressin, tri-cycl-lysine-vasopressin, is a synthetic long-acting analogue of AVP. Terlipressin has a higher affinity for vascular receptors and similar pharmacodynamic properties compared to AVP. Terlipressin is a prodrug that is rapidly metabolized by endothelial peptidases to the vasoactive lysine-vasopressin. The half-life of terlipressin is six hours compared to the short half-life of AVP (six minutes). The pharmacokinetics of terlipressin suggests that an intermittent intravenous dosing schedule of every four to 12 hours would be appropriate, as opposed to continuous infusion of AVP (Pesaturo 2006).

The adverse effects of AVP and terlipressin therapy in human neonates and infants have not been investigated thoroughly. Liver necrosis after AVP (Meyer 2006a), and splanchnic, digital and skin ischemia with terlipressin have been reported (Rodriguez-Nunez 2006; Zeballos 2006).

 

How the intervention might work

AVP mediates the cardiovascular and renal effects via at least three known receptor subtypes (V1, V2 and V3).  AVP exerts a direct vasoconstrictive effect by acting on the V1 receptors that are predominantly found on vascular smooth muscle cells and myocardium. V1 receptors are also found on the hepatocytes and platelets, which may result in platelet aggregation and glycogenolysis during AVP therapy. The receptors are linked to a phosphoinositol signaling pathway with intracellular calcium acting as a second messenger (Holmes 2001). Other probable indirect effects of AVP on vascular smooth muscle cells leading to vasoconstriction include local inhibition of nitric oxide production (Kusano 1997) and inhibition of smooth muscle cell K+-ATP channels (Wakatsuki 1992). When compared with AVP, terlipressin has a greater selectivity for the V1 receptor over the V2 receptor (Nilsson 1990). The rationale for using AVP or terlipressin in refractory hypotension is based on a biphasic response of endogenous AVP in adults with septic shock, with initial high levels followed by inappropriately low levels (Argenziano 1998; Patel 2002). Therefore, in vasodilatory shock, a relative AVP deficiency exists that may be corrected by administration of AVP. Currently, AVP and its analogue, terlipressin, are being increasingly used as a rescue therapy for hypotension refractory to high-dose catecholamine and corticosteroids in neonates with sepsis (Matok 2004; Matok 2005; Leone 2008; Bidegain 2010), cardiogenic shock (Meyer 2006b; Lechner 2007), necrotizing enterocolitis (NEC) (Bidegain 2010), non-septic shock with acute renal injury (Meyer 2006a), and systemic inflammatory response syndrome following surgery (Filippi 2008). In neonatal studies, dosages of AVP ranged between 0.01 to 0.36 units/kg/hour, and terlipressin from 7 µg/kg twice a day to 2 µg/kg every four hours. Terlipressin increases the mean blood pressure by approximately 30% in neonates and infants. The effect was more pronounced in patients who survived than in those who died (Matok 2005; Leone 2008). 

 

Why it is important to do this review

Optimal management of refractory hypotension in high-risk neonates has the potential to improve neonatal outcomes. This review aims to systematically review the literature to investigate the roles of vasopressin and terlipressin in the treatment of refractory hypotension in neonates and to identify gaps in knowledge that will inform future clinical trials.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms
 

Primary objective

To evaluate the efficacy and safety of vasopressin and its synthetic analogues (e.g. terlipressin) in decreasing mortality and adverse neurodevelopmental outcomes, and improving survival in neonates with refractory hypotension.

 

Secondary objectives

To determine the effects of vasopressin and its analogues (terlipressin) on improvement in blood pressure, increase in urine output, decrease in inotrope score (Wernovsky 1995; Lechner 2007), NEC, periventricular leukomalacia (PVL), IVH, chronic lung disease (CLD), and retinopathy of prematurity (ROP) in neonates with refractory hypotension.

We planned to analyze the following subgroups if data had been available.

1. Gestational age:

  • term;
  • preterm (28 to 37 weeks);
  • extremely preterm (less than 28 weeks).

2. Birth weight:

  • birth weight more than 2500 g;
  • birth weight from 1000 to 2500 g;
  • ELBW less than 1000 g.

3. Patient subgroups:

  • sepsis;
  • post-cardiac surgery;
  • NEC.

4. Subgroups of intervention:

  • vasopressin;
  • terlipressin.

5. Severity of hypotension:

  • catecholamine-resistant hypotension;
  • catecholamine and steroid-resistant hypotension.

 

Comparisons

  1. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to standard therapy versus standard therapy alone (combination of volume expansion, catecholamines and corticosteroids).
  2. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to therapy with catecholamines and corticosteroids versus catecholamine and corticosteroids.
  3. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to catecholamines versus catecholamines alone.
  4. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to corticosteroids versus corticosteroids alone.
  5. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to volume expansion versus volume expansion alone.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomized or quasi-randomized controlled trials, cluster-randomized trials or randomized cross-over trials.

 

Types of participants

Any neonate (less than 28 days of age), term or preterm, with refractory hypotension. Refractory hypotension in the newborn is defined as a hypotension with signs of metabolic and lactic acidemia despite volume expansion and administration of inotropic agents and corticosteroids (Sarkar 2007; Baker 2008; Bidegain 2010).

 

Types of interventions

Vasopressin and its analogue terlipressin at any dosage or duration used as an adjunct to standard therapy to treat refractory hypotension in neonates.

Standard therapy of neonatal hypotension is any combination of volume expansion, inotropic agents and corticosteroids.

 

Types of outcome measures

 

Primary outcomes

  1. Efficacy as measured by any of the following:
    1. mortality: 'all-cause mortality' during hospital stay.
    2. survival at 18 or more months of age.
    3. neurodevelopmental outcome assessed by a validated test at 18 or more months of age.

 

Secondary outcomes

    1. Increase in mean blood pressure greater than the 10th percentile for the postmenstrual age (Nuntnarumit 1999) OR increase in mean blood pressure greater than 30 mm Hg in preterm infants, irrespective of their postmenstrual age (Miall-Allen 1987).
    2. Increase in urine output greater than 1 ml/kg/hour over eight hours.
    3. Decrease in inotrope requirements as determined by inotrope score. Scores calculated before and after vasopressin therapy of at least 30 minutes. Inotrope score = dopamine + dobutamine + epinephrine x 100 + norepinephrine x 100, all dosages in micrograms per kilogram per minute (Wernovsky 1995; Lechner 2007).
    4. NEC (definite NEC and perforated NEC, Bell's stage II or III) (Bell 1978).
    5. CLD defined as oxygen requirement at 36 weeks postmenstrual age (Jobe 2001).
    6. PVL (defined as necrosis of white matter in a characteristic distribution, i.e., in the white matter dorsal and lateral to the external angles of lateral ventricles involving particularly the centrum semi ovale, optic and acoustic radiations and diagnosed by magnetic resonance imaging (MRI) (Volpe 2008).
    7. IVH- severe grade III or IV (Papile 1978).
    8. ROP stages III and IV (ICROP 1984).
    9. Safety: Monitored for adverse effects of hyponatremia (serum sodium (Na) less than 130 mEq/L), limb and skin ischemia (evaluated clinically by mottling or discoloration), myocardial ischemia (EKG changes or elevation of cardiac enzymes CPK-MB or troponins).

 

Search methods for identification of studies

We searched the literature using the search strategy recommended by the Cochrane Neonatal Group (CNRG), in January 2012 from the following sources.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library).
  2. Electronic journal reference databases: MEDLINE (1966 to present) and PREMEDLINE, EMBASE (1980 to January 2012), CINAHL (1982 to January 2012).
  3. We searched for ongoing trials in the following databases at the following web sites: www.clinicaltrials.gov and www.controlled-trials.com.
  4. We searched abstracts of conferences - proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Pediatric Research) from 1990 from the journal 'Pediatric Research' and Abstracts online.
  5. We contacted authors who published in this field for possible unpublished articles.
  6. We also searched from the reference list of identified clinical trials and in the review authors' personal files.

Search strategy for MEDLINE and PREMEDLINE. We adapted this strategy to suit EMBASE, CINAHL and the Cochrane Controlled Trials Register.
# 1 explode 'hypotension' [all subheadings in MIME, MJME]
# 2 explode “shock’
# 3 ‘refractory hypotension”
# 4 “catecholamine refractory hypotension”
# 5 'hypoperfusion'
# 6 # 1 or # 2 or # 3 or # 4 or # 5
# 7 explode 'infant - newborn' [all subheadings in MIME, MJME]
# 8 Neonat*
# 9 Newborn*
# 10 # 7 or # 8 or # 9
# 11 # 6 and # 10
# 12 "vasopressin' or pitressin [all subheadings on MIME, MJME]
# 13 terlipressin or glypressin or glycylpressin or remestyp
# 14 # 12 or # 13
# 15 # 11 and # 14

We did not apply language restriction. We sought randomized, quasi-randomized trials, cluster-randomized and cross-over trials from the search results.

 

Data collection and analysis

We followed the standard methods of The Cochrane Collaboration for conducting a systematic review.

 

Selection of studies

Two review authors (BS and MP) independently assessed the titles and abstracts of studies identified by the search strategy for eligibility for inclusion in this review. We obtained the full text version for assessment, if eligibility could not be assessed reliably by title and abstract. We resolved any differences by mutual discussion. We obtained a full text version of all eligible studies for quality assessment.

 

Data extraction and management

We designed electronic forms for trial inclusion/exclusion, data extraction and for requesting additional published information from authors of the original reports. Two review authors (MP and BS) performed data extraction independently using specifically designed electronic spreadsheets. We resolved any differences by mutual discussion.

 

Assessment of risk of bias in included studies

There are no included studies in this version of the review. For future updates of this review, two review authors will independently assess the risk of bias for each study when studies for inclusion are identified, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion with the third review author (CF).

 

(1) Sequence generation (checking for possible selection bias)

If we identify studies that can be included, we will evaluate whether the method used to generate the allocation sequence was described in sufficient detail to allow an assessment of whether it should produce comparable groups. We will assess the methods as:

  • low risk (any truly random process, for example, random number table; computer random number generator);
  • high risk (any non-random process, for example, odd or even date of birth; hospital or clinic record number);
  • unclear risk.   

 

(2) Allocation concealment (checking for possible selection bias)

If we identify studies that can be included, we will evaluate whether the method used to conceal the allocation sequence was described in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We will assess the methods as:

  • low risk (for example, telephone or central randomization; consecutively numbered sealed opaque envelopes);
  • high risk (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
  • unclear risk.   

 

(3) Blinding (checking for possible performance bias)

If we identify studies that can be included, we will describe the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will judge studies to be at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. We will assess blinding separately for different outcomes or classes of outcomes. We will assess the methods as:

  • low risk, high risk or unclear risk for participants;
  • low risk, high risk or unclear risk for personnel;
  • low risk, high risk or unclear risk for outcome assessors.

 

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

If we identify studies that can be included, we will evaluate the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions are reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data are balanced across groups or are related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses. We will assess methods as:

  • low risk;
  • high risk:
  • unclear risk.

 

(5) Selective reporting bias

If we identify studies that can be included, we will investigate the possibility of selective outcome reporting bias. We will assess the methods as:

  • low risk (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
  • high risk (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
  • unclear risk.

 

(6) Other sources of bias

If we identify studies that can be included, we will describe any important concerns we had about other possible sources of bias. We will assess whether each study was free of other problems that could put it at risk of bias:

  • yes;
  • no;
  • unclear risk.

 

(7) Overall risk of bias

We will evaluate the studies using all of the above criteria and make explicit judgements about whether studies are at high risk of bias. With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it likely to impact on the findings. 

If cross-over or cluster-randomized trials are included in future updates of the review, then risk of bias will be assessed as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

 

Measures of treatment effect

We will perform statistical analyses according to the recommendations of the CNRG when data are available. We will analyze all infants randomized on 'an intention-to-treat basis' irrespective of whether they survived or not, to receive their allocated treatment completely. We will analyze treatment effects in the individual trials, using The Cochrane Collaboration's statistical analysis package, Review Manager 5.1 (RevMan 2011).

We will report risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences (MD) for continuous outcomes. With outcomes such as neurodevelopmental outcomes where different scales may be used to measure outcomes, we will report standard MD. If there was a statistically significant reduction in RD then we will calculate the number needed to treat to benefit (NNTB) or number needed to harm (NNTH). We will use a fixed-effect model for meta-analysis.

If cross-over or cluster-randomized trials are included in future updates of the review, then measures of treatment effect will be assessed as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

 

Assessment of heterogeneity

We will assess statistical heterogeneity of treatment effects between trials using the I 2 statistic (RevMan 2011). We will grade degrees of heterogeneity as low (greater than 25%), moderate (greater than 50%) or high (greater than 75%). If significant heterogeneity is noted then we will explore sources of heterogeneity by subgroup or sensitivity analyses.

 

Data synthesis

We will use RevMan 5.1 software (RevMan 2011) for statistical analysis and intend to use a fixed-effect model for meta-analysis when eligible trials are identified.

 

Subgroup analysis and investigation of heterogeneity

    1. Gestational age: term, preterm (28 to 37 weeks), extremely preterm (less than 28 weeks).
    2. Birth weight: birth weight greater 2500 g, BW 1000 to 2500 g, ELBW less than 1000 g.
    3. Patient subgroups: sepsis, post-cardiac surgery, NEC.
    4. Subgroups of intervention: vasopressin, terlipressin.
    5. Severity of hypotension: catecholamine-resistant hypotension, catecholamine- and steroid-resistant hypotension.

 

Comparisons

    1. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to standard therapy versus standard therapy alone (combination of volume expansion, catecholamines and corticosteroids).
    2. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to therapy with catecholamines and corticosteroids versus catecholamine and corticosteroids.
    3. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to catecholamines versus catecholamines alone.
    4. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to corticosteroids versus corticosteroids alone.
    5. Vasopressin and its analogues in the treatment of refractory hypotension in neonates as an adjunct to volume expansion versus volume expansion alone.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms
 

Description of studies

See: Characteristics of excluded studies.

 

Results of the search

We identified three randomized controlled trials of vasopressin (Baldasso 2009; Choong 2009; Rios 2011) and one on terlipressin (Yildizdas 2008) in children. None of the studies met our inclusion criteria. We excluded the studies because there were no neonates in the study population in three studies (Yildizdas 2008; Baldasso 2009; Choong 2009) and treatment of refractory hypotension was not the objective of one study (Rios 2011).

 

Included studies

There are no included studies.

 

Excluded studies

Baldasso 2009

Baldasso and co-investigators evaluated the effects of prophylactic low-dose vasopressin to offset the hypotensive effects of sedation and analgesia in children expected to require mechanical ventilation for more than three days. Twenty-four children were randomized to low-dose vasopressin (0.0005 units/kg/min) or normal saline for a period of 48 hours (12 in each group). Vasopressin infusion was associated with a higher incidence of hyponatremia, decrease in urine output and acute increase in blood pressure. Rebound hypotension was also noticed after stopping vasopressin. This study was excluded as neonates were not included.

Choong 2009

Choong and co-investigators randomized 69 children in vasodilatory shock in a multicenter, double-blind trial to low-dose vasopressin (0.0005 to 0.002 units/kg/min) or placebo. Data from 65 children (33 received vasopressin and 32 placebo) were analyzed. There was no significant difference in the primary outcome of time to vasoactive-free hemodynamic stability or the secondary outcomes of mortality (a trend towards increased mortality in the vasopressin group), organ failure-free days, length of critical care unit stay or adverse events. This study was excluded as neonates were not included.

Yildizdas 2008

Yildizdas and co investigators randomized 58 children (age range one to 156 months) with catecholamine-resistant septic shock to receive either terlipressin (n = 30) or additional catecholamines (n = 28). Terlipressin was administered as intravenous bolus doses of 20 micrograms/kg every six hours if necessary (mean arterial blood pressure was lower than 2 SD (standard deviation)) for a maximum of 96 hours. A combination of at least two catecholamines were administered to all patients in both groups. The outcomes assessed were mean arterial pressure, heart rate, PaO2/FiO2 ratio, duration of mechanical ventilation, blood urea nitrogen, creatinine, alanine aminotransferase, aspartate aminotransferase, urine output, cutaneous and extremity ischemia findings, length of stay, and mortality. Terlipressin improved mean blood pressure and oxygenation 30 minutes after each terlipressin treatment but not mortality rate, urine output, or the duration of mechanical ventilation. Terlipressin use was not associated with any adverse events in this study. This study was excluded as neonates were not included.

Rios 2011

Rios and co-investigators, in a double-blind randomized controlled trial at a single center (Texas Children's Hospital) are investigating the role of vasopressin compared with dopamine for the treatment of low blood pressure in ELBW infants. ELBW infants with a birth weight of < 1001 g and/or gestational age of < 29 weeks, who have hypotension in the first 24 hours of life will be randomized to either a continuous infusion of vasopressin at low, moderate or high doses (0.01 to 0.04 units/kg/hour) or dopamine at low, moderate or high doses (5 to 20 mcg/kg/minute), titrated to target an optimal mean blood pressure value. Outcomes that will be evaluated are achievement of optimal mean blood pressure (primary), 'all-cause mortality', heart rate, serum lactate, sodium and glucose levels, urine output, ischemic changes, feeding intolerance, necrotizing enterocolitis (NEC), intestinal perforation, severity of lung disease, symptomatic patent ductus arteriosus, severe retinopathy of prematurity (ROP), chronic lung disease, intraventricular hemorrhage, periventricular leukomalacia, and neurodevelopmental outcomes. The study started enrolling in March 2011 is expected to complete recruitment in 2013. This study was excluded as the objective of this study was not to treat neonates with refractory hypotension.

 

Risk of bias in included studies

We did not identify any eligible studies for inclusion.

 

Effects of interventions

We did not identify any eligible studies for inclusion.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

We did not identify any completed or ongoing studies that met our inclusion criteria that randomized neonates with refractory shock to vasopressin or its analogues. We identified and excluded three randomized controlled studies in children but not neonates (Yildizdas 2008; Baldasso 2009; Choong 2009) and one ongoing randomized controlled study in neonates where the objective was not to treat neonates with refractory hypotension (Rios 2011).

The randomized controlled trial (Yildizdas 2008) that included children with an age range of one to 156 months suggests that terlipressin can be safely used to increase the mean blood pressure in children with catecholamine-resistant septic shock. Limitations of this study include small sample size and risk of performance bias as the investigators were not blinded to the intervention. Even though terlipressin increased the mean blood pressure, improved oxygenation, and decreased the length of pediatric intensive care unit stay, it had no effects on mortality.

Challenges in summarizing data on vasopressin or terlipressin therapy in neonates include variations in the dose and duration of therapy and the heterogeneous study population in terms of gestational age and underlying disease. Absence of randomized controlled trials complicates unbiased assessment of clinical outcomes including adverse effects. The evidence for the use of vasopressin and terlipressin in neonates is limited to case reports (Matok 2004; Filippi 2008; Stathopoulos 2011) and case series (Matok 2005; Meyer 2006a; Meyer 2006b; Lechner 2007; Leone 2008; Mastropietro 2008; Bidegain 2010; Ikegami 2010; Rodriguez-Nunez 2010;Filippi 2011; Alten 2012). Vasopressin and terlipressin were predominantly used to rescue neonates with catecholamine-resistant and catecholamine- and corticosteroid-resistant hypotension caused by sepsis (Matok 2004; Matok 2005; Meyer 2006b; Bidegain 2010; Rodriguez-Nunez 2010; Filippi 2011), NEC (Bidegain 2010), post cardiac surgery (Lechner 2007; Mastropietro 2008; Alten 2012), systemic inflammatory response syndrome (Filippi 2008), refractory pulmonary hypertension (Filippi 2011; Stathopoulos 2011), and acute kidney injury (Meyer 2006a). The observations from the above studies suggest that vasopressin and its analogue, terlipressin, can effectively increase mean blood pressure both in extremely preterm and term neonates with catecholamine-resistant shock.

Vasopressin or terlipressin-mediated increase in mean blood pressure has not shown to be accompanied by improved survival or increased end-organ perfusion. It is possible that vasopressin or terlipressin were administered to rescue severely moribund neonates late in the disease process. A trend towards increased mortality was observed in children on low-dose vasopressin despite excluding children who were terminally ill or who lacked commitment to life support (Choong 2009). Vasopressin did not consistently improve markers of end-organ perfusion, such as serum lactate, creatinine or urine output and the effects were variable (Matok 2004; Matok 2005; Meyer 2006a; Lechner 2007; Filippi 2008; Mastropietro 2008; Bidegain 2010; Filippi 2011; Alten 2012). The ability of terlipressin and vasopressin to decrease the inotrope score (Lechner 2007; Mastropietro 2008) and the need for catecholamines (Matok 2005; Lechner 2007; Filippi 2008; Mastropietro 2008; Bidegain 2010; Rodriguez-Nunez 2010; Filippi 2011) have been reported. If this is found to be true in well-designed studies, vasopressin or terlipressin can decrease the side-effects associated with high-dose catecholamine therapy, such as arrhythmias, increased myocardial oxygen consumption, and severe vasoconstriction.  

Adverse effects of vasopressin and terlipressin have been reported in some neonatal studies and include hyponatremia (Filippi 2011; Stathopoulos 2011; Alten 2012), cutaneous/limb ischemia (Rodriguez-Nunez 2010), and liver necrosis (Meyer 2006a). Vasopressin or terlipressin use in neonates has not been associated with NEC (Matok 2004; Meyer 2006a; Alten 2012). The safety of vasopressin and its analogues needs to be assessed in prospective randomized controlled studies in neonates. Given the limited experience with the use of vasopressin and its analogues in neonates, it is not surprising that we could not find studies evaluating the effects of vasopressin or terlipressin on the neurodevelopmental outcomes, chronic lung disease, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, and ROP. Further research is needed to clarify the role of vasopressin and its analogues in neonatal refractory hypotension.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

 

Implications for practice

There is insufficient evidence to recommend or refute the use of vasopressin or its analogue, terlipressin, in the safe and effective treatment of refractory hypotension in neonates. Importantly, there is no information about the long-term neurodevelopmental or pulmonary outcomes of neonates treated with vasopressin or terlipressin.

 
Implications for research

Well-designed , adequately powered, randomized controlled studies are necessary to clarify the role of vasopressin and its analogues in neonatal refractory hypotension. Specifically, studies should address the efficacy, safety, indications for their use, timing of therapy, optimal dosing, impact of treatment on major morbidities in preterm infants such as necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, and especially long-term neurodevelopmental, pulmonary outcomes and survival. 

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

This review has no analyses.

 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

Protocol first published: Issue 6, 2011
Review first published: Issue 3, 2013


DateEventDescription

29 October 2008New citation required and minor changesConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

BS and PM carried out the search, identified eligible articles and wrote the review
CF and DR assisted with the search, commented on the review and incorporated comments.
JR commented on the review and helped incorporate comments.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Data and analyses
  9. History
  10. Contributions of authors
  11. Declarations of interest
  12. Sources of support
  13. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.
    Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN275201100016C.

References

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Characteristics of studies
  15. References to studies excluded from this review
  16. Additional references
Baldasso 2009 {published data only}
  • Baldasso E, Garcia PC, Piva JP, Branco RG, Tasker RC. Pilot safety study of low-dose vasopressin in non-septic critically ill children. Intensive Care Medicine 2009;35(2):355-9.
Choong 2009 {published data only}
  • Choong K, Bohn D, Fraser DD, Gaboury I, Hutchison JS, Joffe AR, et al. Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial. American Journal of Respiratory and Critical Care Medicine 2009;180(7):632-9.
Rios 2011 {unpublished data only}
  • Rios DR, Gest AL. Study of dopamine versus vasopressin for treatment of low blood pressure in low birth weight infants. ClinicalTrials.gov 2011:NCT01318278.
Yildizdas 2008 {published data only}

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Characteristics of studies
  15. References to studies excluded from this review
  16. Additional references
Al-Aweel 2001
  • Al-Aweel I, Pursley DM, Rubin LP, Shah B, Weisberger S, Richardson DK. Variations in prevalence of hypotension, hypertension, and vasopressor use in NICUs. Journal of Perinatology 2001;21(5):272-8.
Alten 2012
  • Alten JA, Borasino S, Toms R, Law MA, Moellinger A, Dabal RJ. Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery. Pediatric Critical Care Medicine 2012;13(3):300-4.
Argenziano 1998
  • Argenziano M, Chen JM, Choudhri AF, Cullinane S, Garfein E, Weinberg AD, et al. Management of vasodilatory shock after cardiac surgery: identification of predisposing factors and use of a novel pressor agent. Journal of Thoracic and Cardiovascular Surgery 1998;116(6):973-80.
Baker 2008
  • Baker CF, Barks JD, Engmann C, Vazquez DM, Neal CR Jr, Schumacher RE, et al. Hydrocortisone administration for the treatment of refractory hypotension in critically ill newborns. Journal of Perinatology 2008;28(6):412-9.
Bell 1978
  • Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187(1):1-7.
Bidegain 2010
  • Bidegain M, Greenberg R, Simmons C, Dang C, Cotten CM, Smith PB. Vasopressin for refractory hypotension in extremely low birth weight infants. Journal of Pediatrics 2010;157(3):502-4.
Dempsey 2006
Fanaroff 2006
Filippi 2008
Filippi 2011
  • Filippi L, Gozzini E, Daniotti M, Pagliai F, Catarzi S, Fiorini P. Rescue treatment with terlipressin in different scenarios of refractory hypotension in newborns and infants. Pediatric Critical Care Medicine 2011;12(6):e237-41.
Goldstein 1995
  • Goldstein RF, Thompson RJ, Jr, Oehler JM, Brazy JE. Influence of acidosis, hypoxemia, and hypotension on neurodevelopmental outcome in very low birth weight infants. Pediatrics 1995;95(2):238-43.
Hegyi 1994
Higgins 2011
  • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1 [updated March 2011]. The Cochrane Collaboration. Available from www.cochrane-handbook.org.
Holmes 2001
ICROP 1984
  • The Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. The Committee for the Classification of Retinopathy of Prematurity. Archives Ophthalmology 1984;102(8):1130-4.
Ikegami 2010
Jobe 2001
  • Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American Journal of Respiratory and Critical Care Medicine 2001;163(7):1723-9.
Kusano 1997
  • Kusano E, Tian S, Umino T, Tetsuka T, Ando Y, Asano Y. Arginine vasopressin inhibits interleukin-1 beta-stimulated nitric oxide and cyclic guanosine monophosphate production via the V1 receptor in cultured rat vascular smooth muscle cells. Journal of Hypertension 1997;15(6):627-32.
Lechner 2007
  • Lechner E, Hofer A, Mair R, Moosbauer W, Sames-Dolzer E, Tulzer G. Arginine-vasopressin in neonates with vasodilatory shock after cardiopulmonary bypass. European Journal of Pediatrics 2007;166(12):1221-7.
Leone 2008
  • Leone M, Martin C. Role of terlipressin in the treatment of infants and neonates with catecholamine-resistant septic shock. Best Practice & Research. Clinical Anaesthesiology 2008;22(2):323-33.
Low 1993
Mastropietro 2008
  • Mastropietro CW, Clark JA, Delius RE, Walters HL 3rd, Sarnaik AP. Arginine vasopressin to manage hypoxemic infants after stage I palliation of single ventricle lesions. Pediatric Critical Care Medicine 2008;9(5):506-10.
Matok 2004
  • Matok I, Leibovitch L, Vardi A, Adam M, Rubinshtein M, Barzilay Z, et al. Terlipressin as rescue therapy for intractable hypotension during neonatal septic shock. Pediatric Critical Care Medicine 2004;5(2):116-8.
Matok 2005
Meyer 2006a
  • Meyer S, Gottschling S, Baghai A, Wurm D, Gortner L. Arginine-vasopressin in catecholamine-refractory septic versus non-septic shock in extremely low birth weight infants with acute renal injury. Critical Care 2006;10(3):R71.
Meyer 2006b
Miall-Allen 1987
  • Miall-Allen VM, de Vries LS, Whitelaw AG. Mean arterial blood pressure and neonatal cerebral lesions. Archives of Disease in Childhood 1987;62(10):1068-9.
Munro 2004
Mutlu 2004
Nilsson 1990
  • Nilsson G, Lindblom P, Ohlin M, Berling R, Vernersson E. Pharmacokinetics of terlipressin after single i.v. doses to healthy volunteers. Drugs Under Experimental and Clinical Research 1990;16:307-14.
Nuntnarumit 1999
Osborn 2001
  • Osborn DA, Evans N. Early volume expansion versus inotrope for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 2. [DOI: 10.1002/14651858.CD002056]
Osborn 2004
  • Osborn DA, Evans N. Early volume expansion for prevention of morbidity and mortality in very preterm infants. Cochrane Database of Systematic Reviews 2004, Issue 2. [DOI: 10.1002/14651858.CD002055]
Papile 1978
  • Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. Journal of Pediatrics 1978;92(4):529-34.
Paradisis 2004
  • Paradisis M, Osborn DA. Adrenaline for prevention of morbidity and mortality in preterm infants with cardiovascular compromise. Cochrane Database of Systematic Reviews 2004, Issue 1. [DOI: 10.1002/14651858.CD003958]
Patel 2002
Pesaturo 2006
Pladys 1999
  • Pladys P, Wodey E, Beuchee A, Branger B, Betremieux P. Left ventricular output and mean arterial blood pressure in preterm infants during the 1st day of life. European Journal of Pediatrics 1999;158(10):817-24.
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Rodriguez-Nunez 2006
  • Rodriguez-Nunez A, Lopez-Herce J, Gil-Anton J, Hernandez A, Rey C. Rescue treatment with terlipressin in children with refractory septic shock: a clinical study. Critical Care 2006;10(1):R20.
Rodriguez-Nunez 2010
  • Rodriguez-Nunez A, Oulego-Erroz I, Gil-Anton J, Perez-Caballero C, Lopez-Herce J, Gaboli M, et al. Continous terlipressin infusion as rescue treatment in a case series of children with refractory septic shock. The Annals of Pharmacotherapy 2010;44(10):1545-53.
Sarkar 2007
Seri 2001
Stathopoulos 2011
  • Stathopoulos L, Nicaise C, Michel F, Thomachot L, Merrot T, Lagier P, et al. Terlipressin as rescue therapy for refractory pulmonary hypertension in a neonate with a congenital diaphragmatic hernia. Journal of Pediatric Surgery 2011;46(2):E19-21.
Subhedar 2003
  • Subhedar NV, Shaw NJ. Dopamine versus dobutamine for hypotensive preterm infants. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD001242]
Subhedar 2007
Tsuji 2000
  • Tsuji M, Saul JP, Du Plessis A, Eichenwald E, Sobh J, Crocker R, et al. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000;106(4):625-32.
Volpe 2008
  • Volpe JJ. Hypoxic-ischemic encephalopathy: neuropathology and pathogenesis. Neurology of the Newborn. 5th Edition. Philadelphia: WB Saunders, 2008:347-99.
Wakatsuki 1992
  • Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates K(+)-channel activities of cultured smooth muscle cells from porcine coronary artery. American Journal of Physiology 1992;263(2 Pt 2):H491-6.
Wernovsky 1995
  • Wernovsky G, Wypij D, Jonas RA, Mayer JE Jr, Hanley FL, Hickey PR, et al. Postoperative course and hemodynamic profile after the arterial switch operation in neonates and infants. A comparison of low-flow cardiopulmonary bypass and circulatory arrest. Circulation 1995;92(8):2226-35.
Zeballos 2006
  • Zeballos G, Lopez-Herce J, Fernandez C, Brandstrup KB, Rodriguez-Nunez A. Rescue therapy with terlipressin by continuous infusion in a child with catecholamine-resistant septic shock. Resuscitation 2006;68(1):151-3.